The transition metal cadmium is considered to be a serious occupational and environmental toxin. Cadmium was ranked number 7 on the Agency for Toxic Substances and Disease Registry/Environmental Protection Agency “Top 20 Hazardous Substances Priority List” in 1997 (Fay et al. (1997) Food Chem. Toxicol. 34, 1163-1165). In addition, it is a frequently found contaminant at Superfund sites (Fay et al. (1997) Food Chem. Toxicol. 34, 1163-1165). Cadmium is used primarily in metal coatings, nickel-cadmium batteries and pigments (Friberg et al. (1986) in Handbook of the Toxicology of Metals (Friberg, L, Nordberg G. F. and Vouk, V., ed) pp. 130-237, Elsevier/North-Holland, Amsterdam; Aylett, B. J. (1979) in The Chemistry, Biochemistry and Biology of Cadmium (Webb, M., ed) pp. 1, Elsevier/North-Holland, New York). It is also continuously introduced into the atmosphere through the smelting of ores and the burning of fossil fuels (Friberg et al. (1986) in Handbook of the Toxicology of Metals (Friberg, L, Nordberg G. F. and Vouk, V., ed) pp. 130-237, Elsevier/North-Holland, Amsterdam; Aylett, B. J. (1979) in The Chemistry, Biochemistry and Biology of Cadmium (Webb, M., ed) pp. 1, Elsevier/North-Holland, New York). It has been suggested that increased industrialization has resulted in higher levels of accumulated cadmium in humans (Fortoul et al. (1996) Environ. Health Perspect. 104, 630-632). The primary routes of non-occupational exposure in humans are via inhalation, and ingestion of cadmium-containing food (Waalkes et al. (1992) Crit. Rev. Toxicol. 22, 175-201). Humans are continuously exposed to cadmium and accumulate the metal throughout their lives in liver, lung and kidney tissue (Aylett, B. J. (1979) in The Chemistry, Biochemistry and Biology of Cadmium (Webb, M., ed) pp. 1, Elsevier/North-Holland, New York; Bernard et al. (1986) Experientia Suppl. 50, 114-123). Toxicological responses of cadmium exposure include kidney damage, respiratory diseases, such as emphysema and neurologic disorders (Waalkes et al. (1992) Crit. Rev. Toxicol. 22, 175-201; Chmielnicka et al. (1986) Biol. Trace Elemants Res. 10, 243-256). Cadmium has been classified as a type 1 human carcinogen (Internation Agency for Research on Cancer (1993) Beryllium, Cadmium, Mercury and Exposures in the Glass Manufacturing Industry, Vol. 58, IARC, Lyon). It induces site of exposure, lung, kidney, prostate and testicular cancers in rats and mice (Waalkes et al. (1992) Crit. Rev. Toxicol. 22, 175-201). Human epidemiological data suggests that it causes tumors of the male reproductive system and induces respiratory tumors (Waalkes et al. (1992) Crit. Rev. Toxicol. 22, 175-201; Oberdorster, G. (1986) Scand. J. Work Environ. Health 12, 523-537).
Intracellular damage associated with cadmium exposure includes protein denaturation, lipid peroxidation and DNA strand breaks. Proposed mechanisms by which cadmium induces this damage involve (a) metal binding to reduced cysteine residues and (b) the generation of reactive oxygen species, possibly by lowering reduced glutathione levels (Abe, T. et al. (1994) Biochim. Biophys. Acta. 1201, 29-36;Manca, D. et al. (1991)Toxicology 67, 303-323; Chin, T. A. et al. (1993) Toxicology 77, 145-156). To prevent cadmium-induced intracellular damage, cells respond to metal exposure by inducing the transcription of genes that encode defense and repair proteins. These proteins (a) chelate the metal to prevent further damage, (b) remove reactive oxygen species, (c) repair membrane and DNA damage and (d) renature or degrade unfolded-proteins. Cadmium has been shown to affect the steady-state levels of the mRNAs encoding metallothionein (Hamer, D. H. (1986) Annu. Rev. Biochem. 55, 913-951), heme oxygenase (Adam, J. et al. (1989) J. Biol. Chem. 264, 6371-6375), γ-glutamylcysteine synthetase (Hatcher. E. L. et al. (1995) Free Radic. Biol. Med. 19, 805-812), low and high molecular weight heat shock proteins (Wiegant. F. A. et al. (1994) Toxicology 94, 143-159) and ubiquitin (Muller-Taubenberger, A. et al. (1988) J. Cell Sci. 90, 51-58). In addition, increases in superoxide dismutase, catalase, glutathione peroxidase and glucose-6-phosphate dehydrogenase activities are observed following cadmium exposure in cultured cells and whole animals (Kostic, M. M. et al. (1993). Eur. J. Haematol. 51, 86-92; Salovsky P. et al. (1992) Hum. Exp. Toxicol. 11, 217-222). The mechanism(s) by which this metal modulates the levels of expression of most of these genes remains unknown.
Cadmium-activated transcription may occur through specific metal-responsive upstream regulatory elements found in the promoters of cadmium-responsive genes. These may include metal responsive element (MRE) sequences, found in most metallothionein genes (Stuart, G. W. et al. (1984) Proc. Natl. Acad. Sci. USA 81, 7381-7322; Searle, P. F. (1990) Nucleic Acids Res. 18, 4863-4690; Cizewski Culotta, V. C. et al. (1989) Mol. Cell. Biol. 9, 1376-1380), or cadmium-responsive elements, as found in the human heme oxygenase gene (Takeda, K. et al. (1994) J. Biol. Chem. 265, 14061-14064). Cadmium may also affect gene expression by influencing signal transduction pathways. Cadmium affects the activities of PKC, PKA and calmodulin (Wang, Z. et al. (1998) J. Biol. Chem. 273, 73-79; Beyersmann, D. et al. (1997) Toxicol. Appl. Pharmacol. 144, 247-261). It has been suggested that cadmium-induced transcription of the proto-oncogenes jun and fos is mediated via PKC and calmodulin (Wang, Z. et al. (1998) J. Biol. Chem. 273, 73-79). Thus, cadmium can modulate the activities of complex signal transduction pathways that in turn can influence the expression of a myriad of genes. However, relatively few cadmium-responsive genes have been identified. In addition, there is a paucity of information on the influence of cell-specific and developmental factors on metal-inducible gene expression.